Not applicable.
1. Field of the Invention
The present invention relates to guanidine and biguanidine derivatives which are active as anti-viral agents, specifically having anti-HIV activity. Certain compounds have dual mechanisms of action; i.e. they possess as a single molecular structure both anti-HIV and anti-bacterial activities.
2. Description of the Related Art
Quinolones and azaquinolones are well known antibacterial agents which have been commercially available for more than 20 years under various names like Nalidixic acid, ciprofloxacin, ofloxacin, norfloxacin, lomefloxacin, enoxacin, sparfloxacin, pefloxacin and others. The primary use of these agents is to treat bacterial infection. The first quinolone compound was synthesized in 1976 and its mechanism of action was discovered in 1976, Gellert et al. (Proc. Natl. Acad. Sci., U.S.A., 73, 3872 (1976)). The mode of action of the quinolones is through the inhibition of the bacterial DNA gyrase enzyme. This essential enzyme is a bacterial type II topoisomerase which controls DNA topology and assists with DNA replication, repair, decatenation and transcription. The bactericidal nature of quinolones and azaquinolones is due to their potent inhibition of bacterial DNA gyrase, an enzyme which regulates the supercoiling, uncoiling and spatial geometry of bacterial DNA functions that are necessary for controlling DNA replication and repair, transcription and recombination. Quinolones appear to induce a cellular repair mechanism in these same organisms, leading to unbalanced growth and alteration of cellular structure, which results in the death of the bacterial cell.
DNA gyrase is a type 2 topoisomerase, which has 2A subunits and 2B subunits. These subunits are the target proteins for the quinolones. Mammalian topoisomerase II is highly resistant to inhibition by the quinolones and azaquinolones. Furthermore, the eukaryotic enzyme differs from DNA gyrase by structurally and functionally removing, as opposed to inducing, supertwists into DNA. The bacterial gyrase enzyme is approximately 100 times more sensitive to inhibition than the eukaryotic equivalent.
Quinolones have a paradoxical effect of decreased killing at higher drug concentration. This is because of the fact that at high doses, quinolones inhibit RNA synthesis and protein synthesis. This paradoxical effect of quinolones and azaquinolones are important in designing target compounds against the AIDS virus.
Tetraaza macrocyclic ligands ranging from 12 members to 16 members are known in the literature. For example, the preparation of macrocycles (cyclam) are reported by L. Y. Martin, et al., in J. Am. Chem. Soc., 96, 4046 (1974) and J. Am. Chem. Soc. 99, 2968 (1997). Cyclam is also commercially available from Aldrich. The preparation of bis(macrocycles) is reported by Barefield, E. K., et al., in J. Chem. Soc. Chem. Commun., 302-304 (1981) and Cimpolini, M. et al., in Inorg. Chem., 26, 3527-3533 (1987). These broad families of synthetic macrocyclic and bis(macrocyclic) ligands have been studied not only for their complexation properties with metals but also for their antiviral activities. In the present work, these ligands are used as a template for the guanidine and biguanidine derivatives for their dual mechanism of action as anti-HIV and anti-bacterial activities.
The core structure of the AIDS virus is protected by a lipid layer and highly glycosylated protein (gp 160) which endoproteolytically splits into gp 41 and gp 120. The latter protein binds to CD4 of the T lymphocyte and converts the virus RNA into DNA with the help of the enzyme, reverse transcriptase. The highly balanced hydrophilic-hydrophobic site-specific compounds of the present invention possibly penetrate the viral envelope to reach to the core structure of the AIDS virus and thus act as virucidal-bactericidal agents.
The acquired immunodeficiency syndrome (AIDS) is caused by human immunodeficiency virus (HIV) which is also known by several names, namely HIV-1, LAV (lymphadenopathy-associated virus), HTLV-3 (human T-lymphotropic virus type 3) and ARV (AIDS related virus). The genomes of HIV-1 and HIV-2 are only about 50% homologous at the nucleotide level. Yet the two viruses contain the same complement of genes and appear to attack and kill the same human cells by much the same mechanism. In the US, all the AIDS cases are associated with HIV-1 infections. Since the two viruses, HV-1 and HIV-2 share similar biological properties, they have similar mechanism of action. Both HIV-1 and HIV-2 are retroviruses in which the genetic material is RNA rather than DNA. HIV-1 and HIV-2 viruses may not necessarily cause the death of a patient, but they do, in many cases, cause the patient""s immune system to be severely depressed. This results in various other diseases (secondary infection or tumor formation) such as various bacterial infections (e.g., pneumocystis carinii pneumonia) herpes, cytomegalovirus, Kaposi Sarcoma and Epstein-Barr virus related lymphomas among others. These secondary infections are generally referred to as opportunistic infections. They are separately treated using other medications. There is thus a great need for drugs which are capable of both treating the underlying HIV infection, as well as secondary opportunistic infections.
In one aspect, the present invention relates to a compound having one of the following structures: 
wherein:
a) each A is the same or different, and is selected from the group consisting of i) hydrogen, ii) a nitrile, iii) an amino, iv) an antibacterial agent, v) an antibiotic, vi) a quinolone, vii) an azaquinolone and viii) one of the following groups: 
where R12 is hydrogen or C1-C6 straight or branched alkyl, and R11 is hydrogen, lower alkyl, an aromatic group or a heterocyclic group, with the proviso that with respect to structures I-III, both A""s cannot be the adamantane structure above at the same time;
b) B is a straight chain or branched C1-C30 alkyl group, which may be interrupted by oxygen, sulfur, optionally substituted aromatic nuclei, sulphoxide, optionally substituted cyclohexane, nitrogen optionally substituted with xe2x80x94NHxe2x80x94C (NH)xe2x80x94NHxe2x80x94C(NH)xe2x80x94A where A is defined above, tris (2-aminoethyl) amine, a heterocycle of the following structure: 
where D is 1-3 carbon atoms and Q is hydrogen, halogen or lower alkyl; or 
where Q is hydrogen, halogen or lower alkyl; or 
or a hydrophilic moiety; and
c) R is hydrogen or C1-C6 straight or branched alkyl;
and pharmaceutically acceptable salts thereof.
In another aspect, the present invention relates to a compound having the following structure: 
where each n is independently from 1-5;
Y1 and Y2 are the same or different, and are optionally substituted alkyl; optionally substituted aryl; an optionally substituted heterocycle; or a single bond;
X is optionally substituted alkyl; optionally substituted aryl; or an optionally substituted heterocycle; and
Z is independently xe2x80x94C(NH)xe2x80x94NHxe2x80x94C(NH)xe2x80x94A,
where each A is the same or different, and is selected from the group consisting of i) hydrogen, ii) a nitrile, iii) an amino, iv) an antibacterial agent, v) an antibiotic, vi) a quinolone, vii) an azaquinolone and viii) one of the following groups: 
where R12 is hydrogen or C1-C6 straight or branched alkyl, and R11 is hydrogen, lower alkyl, an aromatic group or a heterocyclic group;
and pharmaceutically acceptable salts thereof.
In another aspect, the present invention relates to a compound having the following structure: 
where each n is independently from 1-5;
each m is independently from 0-12;
each Z is independently xe2x80x94C(NH)NHxe2x80x94C(NH)xe2x80x94A, where each A is the same or different, and is selected from the group consisting of i) hydrogen, ii) a nitrile, iii) an amino, iv) an antibacterial agent, v) an antibiotic, vi) a quinolone, vii) an azaquinolone and viii) one of the following groups: 
where R12 is hydrogen or C1-C6 straight or branched alkyl, and R11 is hydrogen, lower alkyl, an aromatic group or a heterocyclic group,
T is hydrogen, lower alkyl, optionally substituted aryl or optionally substituted heterocycle; and X is from 0-8.
In another aspect, the present invention relates to a compound having the following structure: 
where each A is the same or different, and is selected from the group consisting of i) hydrogen, ii) a nitrile, iii) an amino, iv) an antibacterial agent, v) an antibiotic, vi) a quinolone, vii) an azaquinolone and viii) one of the following groups: 
where R12 is hydrogen or C1-C6 straight or branched alkyl, and R11 is hydrogen, lower alkyl, an aromatic group or a heterocyclic group with the proviso that at least one A is not hydrogen.
In another aspect, the present invention relates to a compound having the following structure: 
wherein each n is independently from 1-5;
m is from 0-3;
each L is independently hydrogen, lower alkyl, optionally substituted aryl, or nitro;
X is CH or N;
each Z is independently xe2x80x94C(NH)NHxe2x80x94C(NH)xe2x80x94A where
each A is the same or different, and is selected from the group consisting of i) hydrogen, ii) a nitrile, iii) an amino, iv) an antibacterial agent, v) an antibiotic, vi) a quinolone, vii) an azaquinolone and viii) one of the following groups: 
where R12 is hydrogen or C1-C6 straight or branched alkyl, and R11 is hydrogen, lower alkyl, an aromatic group or a heterocyclic group.
In another aspect, the present invention relates to a compound having the following structure: 
where m is from 0-4;
each L is independently hydrogen, halogen, alkyl, aryl or nitro;
each W is independently hydrogen, halogen, alkyl, alkoxy, or aryl;
X and Y are each independently CH or N;
Y1 and Y2 are each independently optionally substituted alkyl or a single bond; and each Z is independently xe2x80x94C(NH)xe2x80x94NHxe2x80x94C(NH)xe2x80x94A,
where each A is the same or different, and is selected from the group consisting of i) hydrogen, ii) a nitrile, iii) an amino, iv) an antibacterial agent, v) an antibiotic, vi) a quinolone, vii) an azaquinolone, and viii) one of the following groups: 
where R12 is hydrogen or C1-C6 straight or branched alkyl, and R11 is hydrogen, lowere alkyl, an aromatic group or a heterocyclic group;
and pharmaceutically acceptable salts thereof
In another aspect, the present invention relates to an antiviral composition which comprises:
a) an effective amount of a compound described above; and
b) a pharmaceutically acceptable carrier.
In another aspect, the present invention relates to an antibacterial composition which comprises:
a) an effective amount of a compound described above; and
b) a pharmaceutically acceptable carrier.
In another aspect, the present invention relates to an antiviral and antibacterial composition which comprises:
a) an effective amount of a compound described above; and
b) a pharmaceutically acceptable carrier.
In another aspect, the present invention relates to a method for preventing or treating a bacterial infection in a mammalian host, said method comprising administering to a mammal in need thereof an effective amount of a compound described above.
In another aspect, the present invention relates to a method for preventing or treating a viral infection in a mammalian host, said method comprising administering to a mammal in need thereof an effective amount of a compound described above.
In another aspect, the present invention relates to a method for preventing or treating a viral infection and an opportunistic bacterial infection in a mammalian host, said method comprising administering to a mammal in need thereof an effective amount of a compound described above.
In another aspect, the present invention relates to compounds useful in the synthesis of the compounds of structure (v) above, and which compounds have the following structure: 
where each n is independently from 1-5;
Y1 and Y2 are the same or different, and are optionally substituted alkyl; optionally substituted aryl; an optionally substituted heterocycle; or a single bond;
X is optionally substituted alkyl; optionally substituted aryl; or an optionally substituted heterocycle; and
each Z is independently xe2x80x94C(NH)xe2x80x94NHxe2x80x94CN or xe2x80x94(CH2)mxe2x80x94NHxe2x80x94C(NH)xe2x80x94NHxe2x80x94CN where m is from 1 to 6.
In another aspect, the present invention relates to compounds useful in the synthesis of the compounds of structure (VI) above, which compounds have the following structure: 
where each n is independently from 1-5;
each m is independently from 0-12;
each Z is independently xe2x80x94C(NH)xe2x80x94NHxe2x80x94CN or xe2x80x94(CH2)qxe2x80x94NHxe2x80x94C(NH)xe2x80x94NHxe2x80x94CN where q is from 1 to 6, and
T is hydrogen, lower alkyl optionally substituted aryl or an optionally substituted heterocycle; and X is from 0-8.